Iron deficiency anaemia (Fig. 6.2 and see p. 142) responds to treatment with oral iron supplements – ferrous sulphate 200 mg × 3 daily (or all in one dose) for 6 months – it is essential to give a full course of treatment. Lower the dose if GI symptoms occur. Parenteral therapy is required only rarely. The cause of iron deficiency is almost always blood loss and the cause must be determined.

Figure 6.2 Typical blood film in chronic iron deficiency anaemia. Note the pale red cells with pencil (elongated) cells.

Other causes include:

• Poor diet

• Multiple pregnancies

• Regular blood donation.

Further reading

Provan D. Mechanisms and management of iron deficiency anaemia. British Journal of Haematology. 1999;105(Suppl 1):19–26.

The findings indicate a severe macrocytic anaemia with a moderate neutropenia and thrombocytopenia. The diagnosis could be pernicious anaemia.

Vitamin B₁₂ or folate deficiency impairs DNA synthesis and affects all rapidly dividing cells, particularly in the bone marrow, resulting in pancytopenia when severe. The anaemia is slow to develop and elderly patients, in particular, often do not present until very late.

Avoid blood transfusion, if at all possible, because there is a risk of volume overload and acute left ventricular failure.

Make a precise diagnosis by measuring serum vitamin B₁₂, serum and red cell folate:

• In vitamin B₁₂ deficiency the serum vitamin B₁₂ concentration is always reduced; in folate deficiency the red cell folate concentration is always reduced.

• Severe vitamin B₁₂ deficiency can be associated with a low red cell folate and a normal or high serum folate. Vitamin B₁₂ is required to polyglutamate folate, without which folic acid cannot be retained within cells.

Remember

Drugs and rare metabolic defects can result in megaloblastic anaemia with normal vitamin levels:

• Methotrexate induces functional folate deficiency

• Transcobalamin II deficiency results in intracellular vitamin B₁₂ deficiency (but is very rare).

Bone marrow aspiration (not generally necessary since modern analysers can provide rapid vitamin B₁₂ levels):

• Confirms megaloblastic erythropoiesis

• Documents pretreatment iron stores

• Excludes other conditions – myelodysplasia, acute leukaemia and aplastic anaemia – all of which can present with a macrocytosis and pancytopenia.

Causes

• Folate deficiency? Nutritional deficiency is almost always a factor in any cause of folate deficiency, whether this is due to increased requirements (e.g. myelofibrosis, haemolysis) or to excess alcohol use. In malabsorption, e.g. coeliac disease, there is also poor dietary intake of folate.

• B₁₂ deficiency? Most cases of vitamin B₁₂ deficiency are due to malabsorption, either gastric (because of intrinsic factor deficiency) or intestinal (due to small bowel disease). Pernicious anaemia (antibodies against intrinsic factor) is the most common cause.

Additional investigations

• Intrinsic factor antibody assay (positive in 50% of patients with pernicious anaemia).

• Anti-tissue transglutaminase antibodies and/or jejunal biopsy (to exclude coeliac disease).

• Barium meal and follow-through (to exclude small bowel disease, e.g. Crohn’s disease); in a woman of this age only after the other causes have been excluded.

Many patients with moderate vitamin B₁₂ or folate deficiency have a normal haemoglobin with a raised MCV. Vitamin assays should be performed if the clinical picture is suggestive of a deficiency picture.

• Gastrointestinal disease or surgery including glossitis, malabsorption or diarrhoea

• Neurological disease, including visual loss, a peripheral neuropathy or evidence of demyelination

• Psychiatric disorders including dementia, confusion or depression

• Malabsorption or restricted diets, including vegans and those with anorexia nervosa

• Alcohol excess

• Infertility

• Autoimmune endocrine disease

• Family history of pernicious anaemia

• Drug therapy, particularly anti-convulsants.

Diagnosis.

This patient had megaloblastic anaemia secondary to severe vitamin B₁₂ deficiency.

Pernicious anaemia

• Serum B₁₂: 25 ng/L (NR 160–960 ng/L)

• Serum folate: 14.6 µg/L (NR 4.0–18.0 µg/L)

• Red cell folate: 86 µg/L (NR 160–640 µg/L).

Management

Whenever possible, treat with one haematinic only. In this patient, treat with hydroxocobalamin 1000 µg IM daily for 3 days.

Remember

Never give folate alone because, although it might partially correct the blood abnormalities associated with vitamin B₁₂ deficiency, it will also cause the B₁₂ level to drop even further and might precipitate severe neuropathy.

Do full blood counts + reticulocytes and urea and electrolytes initially daily (in a severely anaemic patient – as in this case) to look for:

• Hypokalaemia, which can occasionally develop 1–2 days post therapy

• Reticulocyte count, which starts to increase 2–3 days after treatment and reaches a peak on days 5–7

• The haemoglobin concentration, which often falls further before starting to rise

• Stay calm! Avoid blood transfusion. Failure of the reticulocyte count and haemoglobin to rise in the predicted manner might be due to:

• Incorrect diagnosis and/or treatment: review laboratory data

• Coexistent iron deficiency: check iron stores, e.g. ferritin levels

• Intercurrent infection: review patient – chest infection? urinary tract infection?

• Coexistent hypothyroidism.

Remember

Pernicious anaemia is an autoimmune disease; 1–2% of patients will also develop thyroid disease. Gastric cancer is also slightly more common (1–3% of cases).

The majority of patients with vitamin B₁₂ deficiency have vitamin B₁₂ malabsorption and require life-long treatment with vitamin B₁₂.

Treatment.

Hydroxocobalamin 1000 µg IM every 3 months is given but high doses of vitamin B₁₂ (2 mg) daily by mouth are also effective.

Nutritional deficiency of vitamin B₁₂ is rare and confined to vegans.

Further reading

Lahner E, Annibale B. Pernicious anaemia; new insights. World J Gastro. 2009;15:5121–5128.

Anaemia due to folic acid deficiency

These patients need 6 months’ treatment with folic acid 5 mg daily after the cause (e.g. coeliac disease, see p. 51) has been defined and treated. Folic acid is, however, ineffective in the treatment of methotrexate toxicity, when folinic acid 15 mg IV daily is given.

Haemolytic anaemia

Haemolytic anaemias are caused by increased destruction of red cells in two sites, intravascular or extravascular.

A normocytic anaemia can be due to:

• Acute blood loss

• Lack of erythropoietin – chronic kidney disease

• Bone marrow infiltration, e.g. carcinoma

• Haemolysis.

The patient described is anaemic and jaundiced with splenomegaly, suggesting a haemolytic anaemia. To confirm this you need to demonstrate:

• Increased red cell production

• A reduced red cell lifespan.

Increased red cell production

• Reticulocytosis: reticulocytes are immature red cells newly released from the bone marrow. They are larger than mature red cells, contain mRNA and appear polychromatic on standard blood films.

• Bone marrow aspiration: erythroid hyperplasia.

Remember

Cortisol, androgens and thyroxine are all required for optimal erythropoiesis.

Reduced red cell lifespan

• Acholuric jaundice: unconjugated hyperbilirubinaemia, urobilinogen but no bilirubin in the urine.

• Abnormal red cell morphology: this might also indicate the specific cause of the haemolytic anaemia (see below).

• Directly by radioactive isotope studies: reduced survival of ⁵¹Cr-labelled autologous red cells (only performed if diagnosis of haemolysis is in doubt).

There are many specific causes of haemolysis. The diagnosis can often be made by review of the blood film. Speak to the haematology medical staff.

Features of haemolysis on blood film

• Spherocytes: autoimmune haemolytic anaemia, hereditary spherocytosis, Clostridium welchii septicaemia, extensive burns

• Red cell fragments: leaking mechanical heart valve, disseminated malignancy

• Sickled cells: sickle-cell anaemia, sickle-cell–HbC disease

• Bitten-out red cells: glucose-6-phosphate dehydrogenase deficiency, unstable haemoglobin, oxidative drug therapy, e.g. Dapsone

• Malaria parasites.

Investigations

• Antibody screen and direct anti-globulin test (DAT): in autoimmune haemolytic anaemia autoantibodies to red cell membrane antigens are present in serum and on the red cell surface

• Urinary haemosiderin: positive in chronic intravascular haemolysis such as paroxysmal nocturnal haemoglobinuria (PNH, very rare) and leaking mechanical heart valves

• Flow cytometry with antibodies against CD55 and CD59 antigens for PNH

• Glucose-6-phosphate dehydrogenase assay: common enzyme deficiency in particular ethnic groups (African, Mediterranean, SE Asian)

This patient had a strongly positive direct anti-globulin test (DAT) with anti-IgG (see Fig. 6.13, p. 129). The antibody eluted from her red cells was also present free in her serum and did not have any easily definable antigen specificity. She therefore has autoimmune haemolytic anaemia (AIHA) due to an IgG red cell autoantibody active at 37°C. AIHA can be primary or secondary. This patient is known to have CLL and has lymphadenopathy and a lymphocytosis with small, mature lymphocytes. Her AIHA is secondary to the underlying chronic lymphocytic leukaemia (CLL); 10–15% of patients with CLL develop AIHA.

Diagnosis.

Autoimmune haemolytic anaemia (secondary to underlying CLL).

Management

• Start oral prednisolone 60 mg/day. This usually produces a remission. Corticosteroids reduce the production of antibodies and also destroy antibody coated red cells.

• Blood transfusion is necessary if the haemoglobin continues to fall. Compatibility testing is complex because the autoantibody interferes with the cross-match; the laboratory could carry out autoabsorption studies to exclude additional alloantibodies. Transfuse slowly.

• Refer patient to her Consultant in Haematology to discuss further management.

Remember

AHA can develop acutely with a rapid fall in haemoglobin. This patient has a short history. Check the haemoglobin concentration at least once a day.

Progress.

This patient went into remission on the steroids. Steroids are effective in about 80% of cases. The haematologists gradually reduced her steroids over 3 months and she was started on azathioprine. A year later her CLL became active and she is now on rituximab and fludarabine.

Sickle-cell disease

Case history

An 18-year-old female of African origin came to A&E with severe pains in her right leg, left hip, chest and back. She was well known to many of the staff as she had attended on many occasions with painful sickle crises. She had been out all night at a club.

The examination should initially be brief until adequate pain control has been achieved.

Questions to ask patients presenting with sickle-cell crises

Treatment of acute painful sickle-cell crises

Analgesia

Morphine/diamorphine

• 0.1 mg/kg IV/SC every 20 minutes until pain controlled, then

• 0.05–0.1 mg/kg IV/SC (or oral morphine) every 2–4 hours

• Patient controlled analgesia (PCA) when pain controlled

• NB Ask patient about previous morphine dosages. Check medical records and discharge summaries. Higher doses may be required in cases who have previously received opioids.

Patient controlled analgesia (PCA) (example for adults > 50 kg)

Diamorphine

• Continuous infusion: 0–10 mg/h

• PCA bolus dose: 2–10 mg

• Dose duration: 1 minute

• Lockout time: 20–30 minutes.

When using diamorphine or other parenteral opiates the following parameters must be monitored regularly on an hourly basis:

• Pain score

• Respiratory rate

• O₂ saturation on air

• Analgesia consumption.

Adjuvant oral analgesia

• Paracetamol 1 g 6-hourly

• +/− Ibuprofen * 400 mg 8-hourly

• or Diclofenac * 50 mg 8-hourly

Supplementary analgesia may be provided by:

Treatment of acute chest syndrome

• Exchange blood transfusion to reduce the amount of HbS to < 20%

• Maintenance of oxygenation: this might include, for example, continuous positive airway pressure (CPAP) via a tight-fitting mask, or intermittent positive pressure ventilation (IPPV)

• Aggressive pain relief

• Intravenous antibiotic therapy.

The majority of patients with a sickle-cell crisis present with severe, acute bone pain secondary to ischaemic bone marrow necrosis. Beware the patient with sickle-cell disease (SCD) who presents unwell but without pain. Such patients might have other, less common, complications of SCD, which can progress very rapidly (Figs 6.3 and 6.4).

Figure 6.3 (a) Osteomyelitis of the humerus in a sickle patient (pre-treatment). Note the elevation of the periosteum at the distal part of the humerus. (b) The same patient showing normal periosteum following treatment.

Figure 6.4 Avascular necrosis of the femoral head in a patient with homozygous sickle-cell disease. There is loss of joint space and distortion of the head of the femur and acetabulum.

Remember

Other complications of SCD include:

• Pneumococcal septicaemia

• Splenic sequestration

• Erythrovirus infection associated with marrow aplasia

• Acute folate deficiency

Progress.

This patient’s current crisis was more severe than her previous ones and she went on to develop the acute chest syndrome from which she died.

Types of sickle-cell disease

• Sickle-cell anaemia HbSS

• Sickle-cell–haemoglobin C disease HbSC

• Sickle-cell beta thalassaemia

• Rare compound heterozygotes, e.g. HbSD.

Diagnosis in A&E/MAU

• Information from patient

• UK Haemoglobinopathy card

• Blood count, reticulocyte count and blood film review

• Serum bilirubin

• Sickle solubility test (commercial kits are available).

Later:

• Haemoglobin electrophoresis (Fig. 6.5) on cellulose acetate membrane (CAM) at an alkaline pH

Figure 6.5 Patterns of haemoglobin electrophoresis.

• High-performance liquid chromatography (HPLC).

Typically, the patient will be anaemic with evidence of haemolysis (elevated bilirubin and reticulocyte count). The blood film will show sickled red cells in variable numbers (Fig. 6.6). The sickle solubility test will be positive and CAM electrophoresis or HPLC will confirm the presence of HbS ± HbC or HbD with no HbA (except in HbS/β⁺ thalassaemia).

Figure 6.6 Blood film in sickle-cell disease showing numerous sickle-shaped red cells.

Beware

• In HbSC and HbS/β⁺ thalassaemia the haemoglobin concentration, reticulocyte count and serum bilirubin can be virtually normal.

• The sickle solubility test is a qualitative test only and will be positive in any individual where the amount of HbS is > 10%. This will include both sickle-cell trait and sickle-cell disease.

Further reading

Rees DC, Williams TN, Gladwin MT. Sickle cell disease. Lancet. 2010;376:2018–2031.

Elevated haemoglobin (polycythaemia)

Case history (1)

On your medical take you admitted a 70-year-old man with breathlessness, wheeze, fever and cough productive of sputum. As a long-standing smoker he suffers bouts of bronchitis but is otherwise in reasonable health.

On examination he was not breathless at rest. Pulse was 82/min with no evidence of cardiac failure. Auscultation of the chest showed scattered wheeze and a few crackles at both bases. Peak flow was 350 L/min.

Initial investigations have shown Hb 230 g/L, PCV 0.62, WCC 12 × 10⁹/L, a mild neutrophilia and platelets 200 × 10⁹/L.

Case history (2)

In the next bed a 54-year-old man has been admitted with chest pain and a suspected myocardial infarct. His general health is reasonable but he has developed severe night sweats and has lost 7 kg over the last 3 months. He denies smoking cigarettes and does not have any previous history of chest problems.

On examination he looked well. Pulse and blood pressure were normal. There were no abnormal signs in the cardiac or respiratory systems.

Investigations show his Hb was 220 g/L with PCV 0.58, WBC 20 × 10⁹/L and platelets 600 × 10⁹/L. Lactic dehydrogenase 740 U/L.

These two cases both have elevated Hb, but is their cause the same?

Haemoglobin (in red blood cells) is required for oxygen transport and, like most things, too much Hb has serious consequences and needs appropriate management (Fig. 6.7).

Figure 6.7 Alteration of haemoglobin in relation to plasma.

How to visualise the Hb level:

• Hb is expressed as a concentration, i.e. g/dL blood but blood = plasma + solids (RBCs mainly). Thus Hb level must be related to the level of the plasma.

Preliminary management

• Ensure no hyperviscosity symptoms or signs:

• Confusion

• Visual disturbance

• Peripheral circulatory disturbance.

• Ensure patient is adequately hydrated.

• Infection (if present) must be treated.

• Identify correctable causes, e.g. chronic hypoxia.

Having made sure that the patients are stable, the next step is to determine the cause of the high Hb concentration. Before carrying out extensive investigation, it is sensible to contact the haematology team, who will either advise on further tests or take over the patient’s care.

The haematology registrar advises you to arrange some investigative tests.

Investigations

• Repeat FBC (to check the result is correct or that with some oral/IV fluid the Hb has normalised). High haematocrit.

• Biochemistry screen: renal function – is it normal? Uric acid – might be high in some types of polycythaemia.

• Blood film: these patients had elevated platelets and WBC – make sure these are normal peripheral blood cells, with no evidence of leukaemia.

• Presence of JAK 2 mutation (see Remember box).

• Bone marrow (see Remember box).

• Erythropoietin levels (normal or low in PV).

Remember

From: Tefferi et al. Blood (2007) 110:1092. American Society of Haematology.

^*EEC. This is not routinely available but colony formation in the absence of exogenous erythropoietin in vitro is 100% specific and sensitve in patients without previous treatment.

For diagnosis of secondary cases

• Blood gases or pulse oximetry (the latter is painless and quite adequate to exclude hypoxia only).

• CXR: emphysema, other lung pathologies.

• Abdominal ultrasound: is the spleen enlarged? Remember renal and uterine causes of polycythaemia.

• Bone marrow: not diagnostic in isolation but gives additional information.

• Erythropoietin levels raised.

NB It is now not necessary to do blood viscosity and red cell volume studies.

Secondary polycythaemia

• As above, but generally with no hepatosplenomegaly, no thrombocytosis.

• Usually secondary cause found, such as cyanotic heart disease, lung disease, renal disease.

Apparent (or relative) polycythaemia

• Red cell mass normal

• Reduced plasma volume

• No hepatosplenomegaly.

Management and progress

This is where knowledge of the underlying cause becomes crucial.

Your FIRST patient has secondary polycythaemia due to lung disease

This is a physiological rise in Hb. Reducing the Hb to normal could have serious consequences because the rise in Hb is a compensatory mechanism.

The initial aim is to reduce the Hb to a safe level. Generally this is achieved by venesection (removal of ~400–500 mL blood) every 2 days. In males the PCV is reduced to < 0.5 and in females to < 0.45.

ALL cases of secondary polycythaemia should be treated with venesection and treatment of the underlying cause if possible. This patient’s raised Hb was due to chronic lung disease, with the high Hb due to hypoxia.

Your SECOND patient has polycythaemia vera (Remember box)

• Venesect 400–500 mL weekly.

• Then control marrow activity with hydroxycarbamide.

• Targeted therapy with JAK1 and JAK2 agonists is becoming available.

Long-term complications

Up to 30% of patients with PV will develop intense marrow fibrosis and 5% develop acute myeloid leukaemia. The other polycythaemias do not transform.

Elevated white blood cell count

Case history

A 17-year-old boy who has ulcerative colitis was admitted to MAU because he felt unwell with a headache, sore throat and a temperature. He had also developed diarrhoea but there was no blood in the stools. He was not on steroids but was on azathioprine 100 mg daily.

On examination his tonsils were enlarged and inflamed; he had palatal petechiae and cervical lymphadenopathy.

Investigations showed an Hb of 124 g/L, an MCV of 98 fL, WBC of 16 × 10⁹/L with abnormal lymphocytes in the peripheral blood. A monospot test is positive.

Diagnosis: Infectious mononucleosis.

There are many causes of a raised WBC (Table 6.1) and there is overlap with haematological malignancies, many of which present with WBC elevation. As a non-specialist confronted with a patient who has an elevated WBC, the key question is: does this elevation represent a haematological malignancy or is it reflecting some other process?

Table 6.1 Causes of high white blood cell counts

Patients with haematological malignancies likely to have high WBC	Situations in which a reactive high WBC occurs
Acute myeloid leukaemia	Infection
Acute lymphoblastic leukaemia	Corticosteroid therapy
Chronic lymphocytic leukaemia	Brisk GI tract bleeding
Chronic myeloid leukaemia	‘Stress’, e.g. postoperative
Lymphoma	Post splenectomy
Other infiltrations: myeloma, myelofibrosis